1. Field of the Invention
This invention relates to the use of chemical substances for the prevention and therapy of mammalian Apicomplexa protozoan parasitic infestations.
2. Description of Related Art
Protozoan parasites of the phylum Apicomplexa include the causative agents of the human disease malaria, as well as the agents of cattle diseases such as Texas cattle fever and East Coast fever. Furthermore, the causative agent of the human disease toxoplasmosis, Toxoplasma gondii, is also found in this phylum. Schmidt, G. D. and Roberts, L. S. Foundations of Parasitology. St. Louis, Times Mirror/Mosby, 1985. pp. 149, 173-178.
Malaria is one of the most important diseases of mankind. Two billion people are at risk of contracting malaria; over 200 million people are infected by the disease, and 3 million people die of malarial infection each year. The disease is caused by four species of plasmodia, Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae. Strains of the most common and most severe causative agent, P. falciparum have developed resistance to many of the current drugs used in treatment, and drug resistance has also been reported in P. vivax. Pudney, M. "Antimalarial: From Quinine to Atovaquone" in: Hunter, P. A., Darby, G. K. and Russell, N. J. Fifty Years of Antimicrobial: Past Perspectives and Future Trends (Cambridge, Society for General Microbiology, 53rd Symposium, 1995), pp. 229-247.
A 35-kb genome of plastid origin has been found in several of the Apicomplexa and it is through to be present in all protozoan species which are members of this phylum. Some Apicomplexa have been shown to be sensitive to members of certain triazine herbicides. This sensitivity is probably due to the interaction of the triazine herbicide with the D1 protein of the photosynthetic reaction center of these parasites organelles. Hackstein, J. H. P., Mackenstedt, U., Mehlhorn, H., Meijerink, J. P. P., Schubert, H., and Leunissen, J. A. M. Parasitic apicomplexans harbor a chlorophyll a-D1 complex, the potential target for therapeutic triazines. Parasitology Research, Vol. 81, (1995), pp. 207-216.
Further research has indicated the 35 kb extrachromosomal DNA of apicomplexan parasites is located in a novel organelle surrounded by four membranes. This suggests that the Apicomplexa parasites acquired this discrete organelle by secondary endosymboisis, probably of a green alga. Kohler, S., Delwiche, C. F., Denny, P. W., Tilney, L. G., Webster, P., Wilson, R. J. M., Palmer, J. D. and Roos, D. S. A Plastid of Probable Green Algal Origin in Apicomplexan Parasites. Science, Vol. 275, (Mar. 7, 1997), pp. 1485-1489.
Replication of the Apicomplexa protozoan parasite T. gondii has been found to be sensitive to inhibition by dinitroaniline herbicides at concentrations which do not inhibit host primary human fibroblasts. Such herbicides are known as specific and potent inhibitors of plant microtubules. Stokkermans, T. J. W., Schwartzman, J. D., Keenan, K., Morrissette, N. S., Tilney, L. G. and Roos, D. S. Inhibition of Toxoplasma gondii Replication by Dinitroaniline Herbicides. Experimental Parasitology, Vol. 84, (1996), pp. 355-370.
The prior art has disclosed the use of chemical agents belonging to the triazine class of herbicides as potential therapeutic agents. Such activity against some apicomplexan parasites is thought to result from interaction of the herbicide with the D1 protein of the photosynthetic reaction center of organelles of the parasites. In addition, dinitroaniline herbicides known to be inhibitors of plant microtubules also inhibit some apicomplexan parasites. The prior art, however, has not disclosed the use of herbicidal agents which inhibit carotenoid synthesis or certain herbicidal agents which inhibit fatty acid synthesis as inhibitors of apicomplexan parasites.